When Pathways Converge: Iron, Lipid Peroxidation, and α-Synuclein in Ferroptosis-Driven Dopaminergic Neurodegeneration.

The selective degeneration of dopaminergic neurons is a hallmark of Parkinson's disease and related disorders. While multiple cell death pathways have been implicated, ferroptosis has recently emerged as a critical mechanism. This iron-dependent form of regulated cell death is driven by the accumulation of phospholipid hydroperoxides, leading to oxidative membrane damage. Dopaminergic neurons are intrinsically vulnerable to ferroptosis due to their high iron content, active dopamine metabolism (a source of reactive oxygen species), and relatively low antioxidant defenses. Here we synthesize evidence linking ferroptosis to dopaminergic neurodegeneration in Parkinson's disease and related conditions, detailing the molecular mechanisms involving iron dyshomeostasis, lipid peroxidation, and α-synuclein pathology. We further evaluate growing preclinical data demonstrating that pharmacological inhibition of ferroptosis is neuroprotective and discuss the clinical implications, therapeutic potential, and ongoing challenges of translating these findings into effective treatments for patients.